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Regional blood flow determinations in the rat during paraoxon-poisoning and treatment with atropine and obidoxime.

Perfusion rates of various organs were determined for 4 different rat populations subjected, respectively, to: (a) 15 min infusion of paraoxon (150 micrograms/kg i.v.); (b) 15 min infusion of paraoxon and the injection of 1.0 mg/kg atropine; (c) 15 min paraoxon infusion and the injection of 10.0 mg/kg obidoxime; and (d) none of these substances. Atropine and obidoxime were both injected 10 min after the beginning of the paraoxon infusion. The perfusion rates were determined by means of the microspheres technique, which allows the simultaneous measurement of different perfusion rates. The paraoxon-treated animals revealed a significantly lower perfusion rate of the kidney, skeletal muscle, skin and spleen in comparison to the unpoisoned control group. The flow rates in heart, stomach, small intestine, liver (arterial) and brain changed only slightly. The injection of atropine caused the perfusion rates of heart, kidney, intestine and spleen to be greater than under paraoxon alone, Obidoxime, furthermore, induced significant increases in the perfusion rates of all 9 organs studied. Indeed, for several organs, the flow rates under atropine and obidoxime were greater than those of the controls. It is suggested that the effects of paraoxon, atropine and obidoxime on the organ flow rates are due to different influences on peripheral and central muscarinic and nicotinic receptors and to changes in the depth of respiration.

Animals↗

Determination of atropine in biological specimens by high-performance liquid chromatography.

A sensitive and selective method for the determination of atropine in biological specimens has been developed. Samples alkalinized with sodium hydroxide were extracted with dichloromethane, and the organic phase was evaporated in a water-bath at 50 degrees C for ca. 10 min. The residue was dissolved in the mobile phase and injected into a reversed-phase column (TSK gel ODS-120A). The retention time for atropine could be varied by changing either the acetonitrile-water ratio in the mobile phase or the pH of the mobile phase. Acetonitrile-water (2:8, v/v) containing 6 mM phosphoric acid was used as mobile phase. Samples of 200 microliters or less were injected into the chromatography and measured at 215 nm. The recoveries of atropine added to drug-free specimens were satisfactory with coefficients of variation of 4% or less. Ninety-two compounds tested did not interfere with the assay of atropine. The method has been applied for monitoring atropine concentrations in cases of organophosphate and drug poisoning.

Adult↗

Improved cardiac risk stratification in major vascular surgery with dobutamine-atropine stress echocardiography.

OBJECTIVES: This study sought to optimize preoperative cardiac risk stratification in a large group of consecutive candidates for vascular surgery by combining clinical risk assessment and semiquantitative dobutamine-atropine stress echocardiography. BACKGROUND: Dobutamine-atropine stress echocardiography has been used for the prediction of perioperative cardiac risk in a small group of patients scheduled for elective major vascular surgery on the basis of the presence or absence of stress-induced regional left ventricular wall motion abnormalities. METHODS: Clinical risk assessment and dobutamine-atropine stress echocardiography were performed in 302 consecutive patients presenting for major vascular surgery. The extent and severity of stress wall motion abnormalities and the heart rate at which they occurred, in addition to the presence of wall motion abnormalities at rest, were assessed. RESULTS: The absence of clinical risk factors (angina, diabetes, Q waves on the electrocardiogram, symptomatic ventricular tachyarrhythmias, age > 70 years) identified a low risk group of 100 patients with a 1% cardiac event rate (unstable angina). Dobutamine-atropine stress echocardiographic findings were positive in 72 patients. Twenty-seven patients had a perioperative cardiac event (cardiac death in 5, nonfatal infarction in 12, unstable angina pectoris in 10); all 27 patients had positive stress test results (positive predictive value 38%, negative predictive value 100%). The semiquantitative assessment of the extent and severity of ischemia did not provide additional prognostic information in patients with positive test results. In contrast, the heart rate at which ischemia occurred defined a high risk group with a low ischemic threshold (38 patients with 20 events [53%]) and an intermediate risk group with a high ischemic threshold (34 patients with 7 events [21%]). All 5 patients with a fatal outcome and 8 of 12 with a nonfatal myocardial infarction were in the high risk group with a low ischemic threshold. CONCLUSIONS: Clinical variables identify 33% of patients at very low risk for perioperative complications of vascular surgery in whom further testing is redundant. In all other candidates, dobutamine-atropine stress echocardiography is a powerful tool that identifies those patients at intermediate risk and a small group at very high risk. Risk stratification with a combination of clinical assessment and pharmacologic stress echocardiography has the potential to facilitate clinical decision making and conserve resources.

Adult↗

Effects of atropine on respiratory sinus arrhythmia (RSA) in the rhesus macaque.

Twelve juvenile to adult rhesus macaques were administered atropine sulfate (0, 14, 44, and 140 mcg/kg IM). The amplitude of the respiratory sinus arrhythmia (RSA) in the rhesus macaque was estimated using a Vagal Tone Monitor (VTM). The estimate of RSA (termed V; vagal tone) was significantly reduced for nearly 3 hr after all doses of atropine, suggesting possible central nervous system effects. Heart period (R-R interval) was reduced briefly after dosing. Overall heart period variability (HPV) was depressed after all doses of atropine. The amount of atropine required to decrease HPV and V by 30% was similar to that reported for the human. The rhesus monkey was determined to have little resting vagal tone as estimated by V. A large slow wave oscillation contributed to the overall variability in heart period. It is concluded that the rhesus monkey exhibits a similar sensitivity to atropine as did the human and, therefore, provides a useful model for the study of cholinergic drug actions and their effects on RSA.

Animals↗

Adenosine-induced bronchoconstriction in human asthmatics: effects of pretreatment with indomethacin or atropine sulfate.

The present investigation was designed to evaluate the effects of pre-treatment with the cholinergic muscarinic receptor antagonist, atropine sulfate, or with the cyclooxygenase inhibitor, indomethacin, on adenosine-induced bronchoconstriction in human asthmatics. Eight male subjects with a FEV1 of greater than 70% of the predicted normal value underwent bronchial provocation challenges with adenosine and with the cholinergic agonist, methacholine, in a double-blind, randomized, cross-over fashion. The log10 of the agonist dose provoking a 20% decrease in FEV1 (log PD20FEV1) was used to assess airways responsiveness. Challenges were performed in the untreated state and 30 min after inhalation of atropine sulfate (0.05 mg/kg). Pre-challenge FEV1 values after atropine inhalation were higher than in the untreated state (p less than 0.01). Without atropine, the log PD20FEV1 values for adenosine were higher than those for methacholine (p less than 0.01). Atropine prevented a decrease in the FEV1 of 20% or more in seven of the eight subjects following inhalation of methacholine up to a concentration of 25 mg/ml, but did not significantly change the log PD20FEV1 for adenosine. The effects of a 75 mg oral dose of indomethacin or placebo, administered in a double-blind, randomized, cross-over fashion two hours before adenosine or methacholine challenge, were assessed in 12 asthmatics. In four subjects (two after placebo and two after indomethacin pretreatment), aerosols of the highest adenosine concentration (10 mg/ml) failed to decrease the FEV1 by 20% or more. In the remaining eight subjects, log PD20FEV1 values for adenosine or methacholine after indomethacin were not significantly different from those after placebo.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗

Protective effect induced by atropine, carbamates, and 2-pyridine aldoxime methoiodide Artemia salina larvae exposed to fonofos and phosphamidon.

The acute toxicity of fonofos and phosphamidon on three age classes of Artemia salina was evaluated. An increase in toxicity of these organophosphorous (OP) insecticides was found following longer development of A. salina. The effects of pretreatment with the nonselective muscarinic antagonist atropine, the two reversible acetylcholinesterease inhibitors physostigmine and pyridostigmine, and the cholinesterase-reactivating oxime 2-pyridine aldoxime methoiodide (2-PAM), as individual and combined pretreatments, on OP-induced lethality in 24 h Artemia were also investigated. The lethal action of both OP insecticides was prevented by pretreatment of 24 h Artemia with atropine and 2-PAM, while physostigmine proved ineffective against intoxication with both OP insecticides and pyridostigmine exhibited a low synergic effect. In both cases, the inhibitory effects of combinations of atropine (10(-5)M) plus 2-PAM were greater than those elicited by either drug alone, with the maximum protection afforded being 100%. Combined pretreatment of atropine (10(-5)M) plus physostigmine practically abolished the lethal effects induced by both insecticides. Pretreatment with 2-PAM (10(-6)M) plus physostigmine afforded maximal protection of 100% and 76% on the lethality induced by fonofos and phosphamidon, respectively. The data obtained suggest that the combination of atropine plus 2-PAM or physostigmine and the combined pretreatment of 2-PAM plus physostigmine are effective in the prevention of the lethal effects induced by fonofos and phosphamidon in A. salina larvae.

Age Factors↗

Fatal Datura poisoning: identification of atropine and scopolamine by high performance liquid chromatography/photodiode array/mass spectrometry.

A forensic method comprising solid phase extraction and HPLC analysis was developed for the detection and confirmation of atropine and scopolamine, the main toxic alkaloids of Datura stramonium and Datura ferox. This method allowed the direct coupling of an electrospray (ZMD) mass selective detector to the HPLC system. Under these conditions, atropine and scopolamine were well separated from other components and detected on the PDA (LOD = 1 microg/ml) and ZMD (LOD(atropine) = 10 pg/ml; LOD(scopolamine) = 100 pg/ml) detectors. Four geographically isolated populations of each of D. stramonium and D. ferox were analysed for seed alkaloids and it was found that the two species were diagnostically different in their atropine-scopolamine ratios. The optimised HPLC method was used to analyse three viscera samples of an adult Caucasian male whose death was ascribed to a fatal heart attack. Atropine and scopolamine were detected in the stomach and its contents, which contained Datura seeds. The chemical profile of the seeds found in the stomach contents was similar to those from four geographically different D. ferox plants.

Adult↗

Fos immunolabelling evidence for brain regions involved in the Pavlovian degraded contingency effect and in its disruption by atropine.

Using a fear conditioning preparation, [Carnicella, S., Pain, L., Oberling, P., 2005a. Cholinergic effects on fear conditioning I: The degraded contingency effect is disrupted by atropine but reinstated by physostigmine. Psychopharmacology 178, 524-532] showed that the muscarinic receptor antagonist atropine disrupted the degraded contingency effect (DCE) in the rat, that is, the processes by which contextual memory competes with cued memory for the control over conditioned responding. Here, we investigated neural substrates involved in the expression of normal and atropine-disrupted DCE, using the protein Fos as a marker of neuronal activity. Compared to contingent conditioning, the DCE was associated with a decrease of the amount of Fos immunoreactive neurons within the auditory system and the amygdala and an increase within the medial prefrontal cortex (mPFC). Compared to the normal DCE, atropine-induced disruption of the DCE was associated with an increase of the amount of Fos immunoreactive neurons within the central nucleus of the amygdala. When atropine-induced suppression of the DCE, Fos pattern was modified in the mPFC with a change in Fos immunoreactivity, but no longer associated with the DCE. However, the mPFC was the unique structure studied in which the amount of Fos immunoreactive neurons was differentially affected according to both the conditioning procedure and the pharmacological treatment. These results are discussed in the framework of the cholinergic modulation of context processing in the rat and are put in parallel with an emerging set of studies in humans regarding the role of the PFC in such processing.

Acoustic Stimulation↗

Atropine for the treatment of childhood myopia.

PURPOSE: To evaluate the efficacy and safety of topical atropine, a nonselective muscarinic antagonist, in slowing the progression of myopia and ocular axial elongation in Asian children. DESIGN: Parallel-group, placebo-controlled, randomized, double-masked study. PARTICIPANTS: Four hundred children aged 6 to 12 years with refractive error of spherical equivalent -1.00 to -6.00 diopters (D) and astigmatism of -1.50 D or less. INTERVENTION: Participants were assigned with equal probability to receive either 1% atropine or vehicle eye drops once nightly for 2 years. Only 1 eye of each subject was chosen through randomization for treatment. MAIN OUTCOME MEASURES: The main efficacy outcome measures were change in spherical equivalent refraction as measured by cycloplegic autorefraction and change in ocular axial length as measured by ultrasonography. The primary safety outcome measure was the occurrence of adverse events. RESULTS: Three hundred forty-six (86.5%) children completed the 2-year study. After 2 years, the mean progression of myopia and of axial elongation in the placebo-treated control eyes was -1.20+/-0.69 D and 0.38+/-0.38 mm, respectively. In the atropine-treated eyes, myopia progression was only -0.28+/-0.92 D, whereas the axial length remained essentially unchanged compared with baseline (-0.02+/-0.35 mm). The differences in myopia progression and axial elongation between the 2 groups were -0.92 D (95% confidence interval, -1.10 to -0.77 D; P<0.001) and 0.40 mm (95% confidence interval, 0.35-0.45 mm; P<0.001), respectively. No serious adverse events related to atropine were reported. CONCLUSIONS: Topical atropine was well tolerated and effective in slowing the progression of low and moderate myopia and ocular axial elongation in Asian children.

Administration, Topical↗

Release of peptide YY by fat in the proximal but not distal gut depends on an atropine-sensitive cholinergic pathway.

Peptide YY (PYY) is released when PYY cells in short term culture are exposed to fat suggesting that this peptide may be released by fat in the distal gut without neural stimulation. PYY is also released by fat in the proximal 1/2 of small intestine. To test the hypothesis that the release of PYY by fat in the proximal but not distal intestine may depend on an atropine-sensitive, cholinergic pathway, PYY levels were compared in four dogs equipped with duodenal and mid-intestinal fistulas when 60 mM oleate was perfused into either the proximal (between fistulas) or distal (beyond mid-intestinal fistula) 1/2 of gut at 2 ml/min for 120 min with intravenous administration of saline or atropine. We found that, when fat was confined to the proximal 1/2 of the intestine, PYY release was reduced following intravenous atropine when compared with saline (p<0.01). However, when fat was confined to the distal 1/2 of the intestine, PYY release was not affected by the intravenous atropine. We conclude that PYY release by fat in the proximal but not distal intestine depends on an atropine-sensitive, cholinergic pathway.

Adipose Tissue↗

Effects of vagal stimulation, atropine, and propranolol on fibrillation threshold of normal and ischemic ventricles.

The effects of electrical stimulation of the vagus nerves and the administration of atropine on ventricular fibrillation threshold (VFT) were studied in open-chest hearts of 15 dogs anesthetized by alpha-chloralose. These studies were made in both normal and ischemic ventricles, i.e., before and during acute coronary occlusion. The ventricles were paces at a constant rate to eliminate rate-dependent changes and the minimal current required to induce ventricular fibrillation (or VFT) was determined by delivering a train of rapid rectanglular pulses (100 per second) to the venticle actoss the vulnerable period. In normal ventricles, VFT's were significantly increased by vagal stimulation (P less than 0.01) and decreased by atropine (P less than 0.05). Coronary occlusion markedly decreased VFT's (P less than 0.01), and vagal stimulation or atropine failed to alter VFT's significantly in these ischemic ventricles (P greater than 0.8). In additional 14 dogs, the effects of vagal stimulation and atropine were studied after the administration of propranolol. Propranolol alone increased VFT's significantly in boetreatment with propranolol, vagal stimulation and atropine failed to change VFT's significantly in both normal and ischemic ventricles (P greater than 0.8). These results indicate that the vagus nerves exert their effect on VFT by modifying the sympathetic nerve activity in normal ventricles, but such an effect is not significant enough to alter VFT in ischemic ventricles.

Animals↗

Usefulness of low doses of atropine to quantify the vagal stimulus-response relation in patients with congestive heart failure.

The response of low doses of atropine is reported to be attenuated in patients with congestive heart failure (CHF). Judging from the main site of action of low doses of atropine, we may be able to assess the functional state of the vagal center in the central nervous system. This study examines the clinical significance of heart rate (HR) response to a low dose of atropine in patients with CHF. Low and high doses of atropine were administered intravenously in 72 patients with CHF. HR after a low (parasympathomimetic) dose injection was assessed by the ratio Rm (minimal HR/basal HR), and after a high (parasympatholytic) dose by the ratio R1 (augmented HR/basal HR). Rm and R1 were related to indexes of CHF. Rm increased with progression of CHF (0.92 +/- 0.03 in New York Heart Association functional class I, 0.98 +/- 0.05 in class II, and 1.00 +/- 0.04 in class III). It also correlated with ejection fraction (r = -0.48, p <0.01) and more importantly, with peak oxygen uptake (r = -0.59, p <0.01). R1 exhibited weak correlation with basal HR (r = -0.33, p <0.05) and ejection fraction (r = 0.31, p <0.05), but had no correlation with other indexes. The vagal center may be already blunted in New York Heart Association class II with respect to increased Rm, which may be related to depressed exercise capacity. A low dose of atropine injection offers a simple and safe method for providing important information on the functional state of the vagal center in the central nervous system in patients with CHF.

Adult↗

The effects of fiberoptic bronchoscopy with and without atropine premedication on pulmonary function in humans.

Pulmonary function studies, including arterial blood gas analysis, were performed in 21 patients undergoing fiberoptic bronchoscopy. Eight received premedication with atropine and 13 did not. In the atropine-treated group there was no significant deterioration in pulmonary function immediately after bronchoscopy compared with baseline. Compared with the values obtained after topical lidocaine anesthesia, however, there was a decrease in peak expiratory flow rate (PEFR) (20 +/- 20%), forced expiratory volume in one second (FEV1.0) (11 +/- 12%), forced expiratory flow between 25 and 75% of vital capacity (FEF25-75) (22 +/- 16%), and forced expiratory flow at 75% of exhaled vital capacity (FEF75) (28 +/- 38%) and an increase in residual volume (RV) (16 +/- 19%). In the no-atropine group, postbronchoscopy values showed a decrease in PEFR (13 +/- 19%), forced vital capacity (FVC) (13 +/- )9%), FEV1.0 (14 +/- 16%), and oxygen partial pressure (Pa02) (11 +/- 9%) and an increase in RV (19 +/- 31%) and alveolar-arterial oxygen pressure gradient (deltaAaPO2) (91 +/- 129%) compared with baseline values. In this group also, topical lidocaine anesthesia resulted in a decrease in FVC compared with baseline. We conclude that the deleterious effect of bronchoscopy on pulmonary function is counterbalanced by the beneficial effect of atropine and that atropine is therefore a useful premedication for fiberoptic bronchoscopy.

Adolescent↗

Transfer between atropine-induced spiking in the perirhinal cortex and electrical kindling of the amygdala.

We have recently determined that microinfusions of atropine sulphate into the perirhinal cortex (PRC) of adult Sprague-Dawley rats result in the dose dependent generation of epileptiform spike activity. Several observations suggested that atropine-induced spiking (AIS) and amygdaloid kindled seizures may share common neuronal mechanisms: (a) PRC atropine infusions occasionally resulted in the development of generalised seizures resembling those produced by amygdaloid kindling and which were accompanied by simultaneous discharge recorded from the PRC and amygdala, and (b) concurrent low amplitude spiking was occasionally recorded from the amygdala during non-seizure inducing infusions. Using kindling transfer, the present study sought to determine whether AIS possesses some epileptogenic characteristics which are common to an electrically generated afterdischarge. Repeated PRC infusions of atropine sulphate supra-threshold for the elicitation of spiking appeared to produce a positive transfer in that significantly more advanced behavioural seizures were elicited during initial amygdaloid kindling. These findings suggest that AIS (and/or atropine-induced behavioural seizures) and amygdala-kindled seizures share, at some level, common neuronal mechanisms.

Amygdala↗

5-Hydroxytryptamine and atropine inhibit nicotinic receptors in submucosal neurons.

The whole-cell recording technique was used to investigate the pharmacological properties of acetylcholine-activated ion channels of cultured submucosal neurons from guinea-pig small intestine. Acetylcholine induced whole-cell membrane currents (I(ACh)) in a concentration-dependent manner (EC(50)=79 microM). I(ACh) exhibited strong inward rectification, had a reversal potential of +19+/-2 mV (Na(+) outside, Cs(+) inside), was reversibly inhibited in a concentration-dependent manner by hexamethonium (EC(50)=5 microM) and atropine (EC(50)=1.6 microM), and was unaffected by alpha-bungarotoxin (30 nM). Atropine was less potent in inhibiting the currents induced by 30 microM acetylcholine than those induced by 1 mM acetylcholine. I(ACh) was mimicked by the current induced by nicotine (I(Nic); EC(50)=52 microM). I(Nic) was also blocked by atropine (EC(50)=1.7 microM) and hexamethonium (EC(50)=3.6 microM). 5-Hydroxytryptamine (5-HT) also inhibited I(ACh) in a concentration-dependent manner (EC(50)=180 microM) in the experiments carried out in the presence of a 5-HT(3) receptor antagonist. 5-HT had a similar inhibitory effect after the desensitization of 5-HT(3) receptors or in neurons with relative small 5-HT(3)-mediated currents. The inhibitory actions of hexamethonium, atropine, and 5-HT on I(ACh) were voltage-dependent. Thus, inhibition was significantly smaller for outward currents (recorded at +40 mV) than for inward currents (recorded at -60 mV). Our observations indicate that the I(ACh) of submucosal neurons are mediated by activation of nicotinic channels, which are blocked by atropine, 5-HT, and hexamethonium. The possibility that one of the 5-HT roles in the gastrointestinal tract might be to directly modulate nicotinic channels is discussed.

Acetylcholine↗

Atropine acts in the ventral striatum to reduce raclopride-induced catalepsy.

While muscarinic receptor antagonists are used to reduce motor side effects associated with the use of antipsychotic drugs, their site of action remains unclear. The study investigated the site of action of the non-selective muscarinic receptor antagonist atropine on catalepsy induced by the selective dopamine D2 receptor antagonist, raclopride. Initially, catalepsy and striatal muscarinic receptor occupancy was assessed 2 h following subcutaneous injection of raclopride and either atropine or vehicle. Catalepsy was significantly reduced by doses of atropine that occupied more than 69% of muscarinic receptors. Next, atropine was injected bilaterally into the ventral striatum, which produced a significant reduction in catalepsy, while injections into the dorsal striatum and substantia nigra had no effect. The site of atropine's action was localised to a discrete area of the ventral striatum through the use of quantitative autoradiographic techniques. These findings provide further evidence for the importance of the ventral striatum in the expression of behaviours.

Animals↗

Limited benefit of atropine as premedication for colonoscopy.

A prospective double-blind trial was performed comparing atropine (0.5 mg) by slow intravenous administration to placebo as premedication for colonoscopy, to assess the possible beneficial effects of this vagolytic agent on the performance and safety of the procedure. A total of 77 patients was randomly assigned to receive atropine (38 patients) or placebo (39 patients) before colonoscopy in conjunction with our standard initial medications for conscious sedation (meperidine, 0.4 mg/kg and midazolam, 0.03 mg/kg). Total procedure time was 31 min for the atropine group and 35 min for the placebo group (p greater than 0.05), and there was no overall difference in the total amount of intra-procedural medications required. No statistically significant differences were observed relative to the number or severity of vagal episodes, and neither the endoscopist nor the patients noted any differences in the ease or tolerance of the procedure (p greater than 0.05). Although these results fail to demonstrate a significant benefit of atropine when given routinely as premedication for colonoscopy, this study does not rule out the potential usefulness of atropine in counteracting vagal episodes when they occur.

Arrhythmias, Cardiac↗

Enantioseparation of atropine by capillary electrophoresis using sulfated beta-cyclodextrin: application to a plant extract.

A capillary zone electrophoresis (CZE) method, with sulfated beta-CD as chiral selector, was optimized by means of an experimental design for the enantioseparation of atropine. In this study, a central composite design was used and the following factors were varied simultaneously: buffer concentration, buffer pH and sulfated beta-CD concentration. The resolutions between littorine and its positional isomer ((-)-hyoscyamine) and between atropine enantiomers, as well as the separation time and generated current were established as responses. A model was obtained for each response by linear multiple regression of a second-degree mathematical expression. The most favorable conditions were determined by maximizing the resolution between atropine enantiomers and by setting the other responses at threshold values. Successful results were obtained with a 55 mM phosphate buffer at pH 7 in the presence of 2.9 mM sulfated-beta-CD at 20 degrees C and 20 kV. Under these optimized conditions, a baseline separation of littorine and atropine enantiomers was achieved in less than 5 min. Finally, the method allowed the enantiomeric separation of atropine in a pharmaceutical formulation and was also found to be suitable for the enantiomeric purity evaluation of (-)-hyoscyamine in plant extracts, in relation with the extraction procedure. It was demonstrated that supercritical fluid extraction induced less racemization than classical liquid-solid extraction procedures.

Atropine↗